Process for the manufacture of pentoses



Patented Sept. 4, 1945 STATES PATENT OFFICE PROCESS FOR THE MANUFACTURE OF PENTOSES John Lee, Essex Fells, Ulrich V. Solmssen, Clifton,

and Leo Berger, Nutley, N. 1.,

alsignors to Hoflmann-La Roche, Inc., Nutley, N. 1., a corporation of New Jersey No Drawing. Application September 30, 1943, Serial No. 504,443

(Cl. (F-209) 8 Claims.

This invention relates to an improvement in the manufacture of pentoses, such as ribose, lyxose, xylose and arabinose, especially of pure pentoses from crude mixtures containing pentoses described another class of N-pentosides which are formed in solution by condensation of a primary aromatic amine and a pentose with application of heat. We have stated in our copending application that in order to demonstrate the fact In the large scale production of ribose it was that the two N-pentosides represent diil'erent hitherto necessary to isolate the sugar from crude classes, we compared the compound formed by reaction mixtures containing it; for example, heating together ribose and 3,4-dimethylaniline from reduction products of ribonolactone and in alcoholic solution, as described by Kuhn and from natural hydrolysates of nucleic acid, nu- 10 Birkofer in Ber. 71, 629 (1938), with the comcleotidesandnucleosides. The procedure usually I pound resulting from the condensation of the involves an extensive purification of the solutions components at room temperature according to and, in most cases, the subsequent isolation of our process. The former has the probable forthe ribose by means of its derivatives with, for mula of a furanoside: instance, the expensive bromophenylhydrazine Q or diphenylhydrazine. Moreover, bromophenvl- OH OH hydrazine is unstable and therefore unsuited for I 4} A: technical scale operations. The hydrazones ob- CK I tained must be isolated and purified. These are 1i a then hydrolyzed in the presence of formaldehyde I o or benzaldehyde. The hydrazones of these aldeand the characteristics E +172 (c o'5 m pyridine), M. P. 128-130 whereas the probable hydes (as well as excess of the aldehydes them- 1 f d is that of a pyranoside. selves which must be employed) must then be formu our compoun removed. This latter operation often presents CHI considerable difllculties, repeated extraction treatment being necessary. Such processes are CH also unsatisfactory from the point of view of yield and the ribose obtained by them is usually syrupy o and requires considerable treatment to obtain a Y fi f mfifg +53 0 crystalline form In'the process described by We have discovered that both classes of N- Fischer and Piloty, Ber. 24, 4214 (1891) and furribosides can be hydrolyzed to give excellent ther modified by Steiger, Helvetica Chimica Acta yields of pure ribose Hydrolmtion can be f- 19, 193 (1936), the complex nature of the above fected by refluxing the Nmentoside in aqueous procedure is illustrated or aqueous alcoholic solution or suspension until By our impmvement' ribose can be isolated the hydrolysis is complete, as can be determined starting from a relatively impure crude material if necessary by l flm tri observation The in a manner which, in sharp contrast to the state preferred pH range for the hydrolysis i fr the is mpid' simple and inexpensive about 2 to about 9, and the decomposition of the can? N-pentoside may be facilitated by binding the In our copending application, Ser. No. 504,442, liberated amine to an ldehyde present during filed of even date herewith. we have described and the reaction, such as b nzgldehyde, substituted claimed a new class n'penwsides which are aromatic benzaldehydes, formaldehyde and the characterized by ease of formation, by condensa- 111% w may also advantageously add a small mm of a Primary aromatic amine and the Penmse quantity of a volatile lower fatty acid, such as in solution at room temperature at a pH of from fomic acetic or proplonic acid, or traces of about 2 to about 3, and especially y the fact that strong acids, although the latter cause some deh y ry allize ir ly in od yi n r composition of the ribose. The presence of a easily p ate m e 8011111 0 Sometimes in non-oxidizing atmosphere is advantageous. This the form of complexes with soluble alkali metal can be accomplished by displacing the air with or ammonium salts. We point out in the co- C0; or No. pending application that this strong tendency to Hydrolyzation and removal of the amine may separate from solution is apparent even where he carried out by other means, as, for example, the solutions of the sugar are relatively impure. by steam distillation of an'aqueous solution or Kuhn and Birkofer in Ber. 71, 629 (1938) have suspension of the N-riboside; the liquors on evaporation yield ribose. In this case, the reaction is carried out in the presence of a weak base, as the primary amine liberated forms a slightly alkaline solution. By steam distillation we mean steam distillation under pressure or under vacuum; we also include steam distillation in an atmosphere of inert gas.

We have furthermore found that the complex compounds of N-ribosides and water-soluble salts of alkali metals or of ammonium, which are described in our aforementioned copending application Ser. No. 504,442, can be satisfactorily used in the above operations insteadmf pure N-ri-bosides. By complexes of the ribosides we mean the ribosides conforming to the above description with a greater or lesser proportion of salt of an alkali metal or ammonium salt, as, for example, sodium sulfate, sodium chloride, sodium nitrate, sodium citrate, sodiumacetate, sodium phosphate, ammonium chloride and the like, and water or other solvent of crystallization. In this case, the aqueous solution after removal of the amine is evaporated to dryness and the ribose removed by extraction from the salt by a suitable solvent such as alcohol. Alternatively, the complex which contains sumcient water for the hydrolysis can be suspended in alcohol and the hydrolysis performed in the presence of benzaldehyde as described. The insoluble salt is then filtered oil, water added, the alcohol removed and the benzal compound eliminated in the usual manner. We have found that the process is especially valuable since the complex salts can be obtained in very high yield.

The recovery of the aromatic amine from the condensation products after or even during hydrolysis provides for our process the additional advantage of convenience and reduction in cost of operation.

Suitable N-ribosides for use in our invention are aniline ribosides. alkoxyaniline ribosides, chloraniline ribosides, naphthylamine ribosides, hydroxyaniline ribosides, toluidine ribosldes and xylidine ribosldes, as, for example, aniline-N-dri bofuranoside, aniline-N-d-ribopyranoside, ochloraniline-N-d-ribopyranoside, anisidine-N-dribofuranoside, 3,4 dimethylaniline-N-d-ribofuranoside, 3,4-dimethylaniline-N d ribopyranoside, o-hydroxyaniline-N-d-ribopyranoside, p

toluidine-N-d-ribopyranoside, a-naphthylamine- N'd-ribopyranoside and their 2,3,4-triacetyl derivatives, 2,3,4-tribenzoyl derivatives, 2,3,5 -triacetyl derivatives and 2,3,5-tribenzoyl derivatives as, for example. a-trlacetyl-aniline-N-d-ribofuranoside and a-triacetyl-aniline-N-d-ri-bopyranoside.

The invention is illustrated by the following examples without intending to limit the scope of the invention thereto.

Example 1 16 g. a-aniline-d-ribopyranoside-sodium sulfate complex, equivalent to 7.92 g. pure riboside, are dissolved in 200 cc. of water containing 0.25% acetic acid. The air is displaced from the apparatus by means of nitrogen and the solution is steam distilled under an atmosphere of nitroen until all the aniline is removed. The residue remaining is stirred with 0.5 g. norite, filtered and evaporated to dryness in vacuum. The residue is extracted twice with warm absolute alcohol, filtered and evaporated to dryness. The syrup crystallizes immediately on seeding with a crystal of D-ribose. M. P. 84-6".

By norite we mean the commercially available decolorizing carbon of that name, but any carbon with similar characteristics may be used.

Example 2 29 g. a-aniline-d-ribopyranoside-sodium sulfate complex, containing 70% riboside, is suspended in cc. of water and 17.5 cc. fresh benzaldehyde added. The mixture is refluxed under an atmosphere of nitrogen gas for hour and cooled. The benzalaniline is removed by extracting with ether, the aqueous residue decolorized with a little carbon, evaporated to dryness and recrystallized from alcohol. The yield is Example 4 4.0 g. a-aniline-d-ribopyranoside is dissolved in 200 cc. of water containing 0.25% acetic acid. The solution is steam distilled under an atmosphere of carbon dioxide until all the aniline is removed and the solution is treated with 0.25 g. of norite, stirred and filtered. The clear solution, on evaporation to dryness, recrystallizes from 4 cc. absolute alcohol yielding 2.3 g. of pure crystalline ribose, 86.2%.

Ri bose may also be prepared from a-anilined-ribopyranoside by hydrolysis in the presence of benzaldehye as described in Example 2.

Example 5 10 g. a-aniline-d-ribopyranoside (M. P. -7"; [a] -+63.4 +48.6) is dissolved in 80 cc. boiling absolute alcohol, refluxed for one hour and cooled. Crystallization occurs, and, after washing with cold absolute alcohol and ether, the yield is 9.9 g. of a-aniline-N-d-ribofuranoside. M. P. 138-40". [l ="=+176.5 +l56.6 (c=3.0 in pyridine) 4.0 g. a-aniline-d-ribofuranoside is dissolved in 200 cc. water containing 0.25% acetic acid and the solution steam distilled under an atmosphere of nitrogen. When all the aniline is removed the.

residual solution is decolorized with 0.25 g. of norite, filtered and evaporated to dryness under vacuo. The residue is taken up twice in absolute alcohol and evaporated to dryness. The resultant syrup is dissolved 'in 4 cc. absolute alcohol, from which 2.4 g. of ribose crystallizes immediately. M. P. 86-7. [al ="=-19.6.

Example 6 45 g. a-aniline-N-d-ribofuranoside is suspended in 2250 cc. water in a 5-liter, 3-neck flask provided with a. stirrer and condenser. The reaction mixture is heated until the glycoside dissolves, and at this point 35 cc. benzaldehyde are added. The mixture is refluxed under nitrogen for /2 hour, cooled overnight and benzalaniline filtered oil. The aqueous residues are extracted with COMPOUNDS.

ether to remove final traces of benzalaniline, decolorized with norite and evaporated to a syrup. The syrup is then dried by taking up in alcohol andfeeevaporated and dissolved in alcohol in the ratio of g. syrup to 6.5 cc. alcohol. 0n seeding, ribose crystallizes out in 95% yield. M. P. 86-7.

From the liquors of crystallization, a-aniline- N-d-ribofuranoside-sodium salt complex can be prepared according to our patent application Ser. No. 504,442, and this again re-worked for ribose.

In a similar manner to the above, a-3,4-dimethylaniline-N-d-ribofuranoside can be hydrolyzed to yield ribose.

While our above examples are limited to an 11- lustration of the application of our hydrolyzation method to aromatic amine N-ribosides made from impure ribose, it is to be understood that the method is equally applicable to other N-pentosides, such as those from lyxose, xylose and arabinose. In our aforementioned copending application Ser. No. 504,442, we have described the s-aniline-N-d-arabinopyranoside as well as N- ribosides prepared from substantially pure sugars.

In the description and in the appended claims,

by ribosides we mean the obviously equivalent aand p-ribopyrano-sides or 02- and ,s-ribofuranosides; we also mean that these ribosides may be in the d orl form.

What we claim is:

1. Process for the manufacture of a pentose from a primary aromatic amine N-pentoside which process comprises heating a primary aromatic amine N-pentoside in solution at a pH range of from about 2 to about 9 in the presence of water until hydrolysis is substantially complete, separating the primary aromatic amine set free and isolating the pentose from the aqueous solution by evaporation.

2. Process for the manufacture of a pentose from a primary aromatic amine N-pentoside which process comprises heating an aniline N- pentoside in solution at a pH range of from about 2 to about 9 in the presence of water until the hydrolysis is substantially complete, separating the amine set free and isolating the pentose from the aqueous solution by evaporation.

3. Process for the manufacture of a pentose from a primary aromatic amine N-pentoside which process comprises heating a-aniline-N-dlllllllmol pentopyranoside in solution at a. pH range of from about 2 to about 9 in the presence of water until the hydrolysis is substantially complete, removing the amine set free by means of benzaldehyde and isolating the pentose from aqueous solution by evaporation.

4. Process for the manufacture of ribose which comprises heating a-aniline-d-ribopyranoside-sodium sulfate complex in aqueous alcoholic solution in the presence of benzaldehyde until hydrohrsis is substantially complete, cooling the solution, filtering from sodium sulfate, diluting the filtrate with water and extracting it with ether, and isolating the ribose from the remaining aqueous solution.

5. Process for the manufacture of ribose which comprises heating a-aniline-N-ribofuranoside in solution at a pH range of from about 2 to about 9 in the presence of water until the hydrolysis is substantially complete, removing the amine set free by steam distillation and isolating ribose from the aqueous solution by evaporation.

6. Process for the manufacture of ribose which comprises heating a 3,4-dimethylaniline-N-riboside in solution at a pH range of from about 2 to about 9 in the presence of water until the hydrolysis is substantially complete, separating the amine set free and isolating the ribose from the aqueous solution by evaporation.

'7. Process for the manufacture of ribose which comprises heating a-3,4-dimethylaniline-N-dribofuranoside in aqueous solution at a pH range of from about 2 to about 9 until the hydrolysis is substantially complete, removing the amine set free by steam distillation and isolating ribose from the aqueous solution by evaporation.

8. Process for the manufacture of a pentose from a primary aromatic amine N-pentoside which process comprises heating the complex compound of a primary aromatic amine N-pentoside with a soluble salt selected from the group consisting of alkali metal salts and ammonium salts in solution in the presence of water at a pH range of from about 2 to about 9 until hydrolysis is substantially complete, separating the primary aromatic amine set free and isolating the pentose from the aqueous solution by evaporation.

JOHN LEE. ULRICH V. SOLMSSEN. LEO BERGER. 

